Treating Inflammatory Bowel Disease During Pregnancy: Risks and Safety of Drug

Therapy

Abstract:

The safety of drug therapy for inflammatory bowel disease during pregnancy is an important
clinical concern. Current available information is largely derived from animal studies and
clinical experience among patients with inflammatory bowel disease and autoimmune disorders
and organ transplant recipients. However, these data are confounded by various factors including
difficulty projecting the results of animal studies to humans, methodological deficiencies of
some studies, insufficient experience with certain agents, difficulty distinguishing the fetal
effects of underlying disease from drug therapy and a need to consider the impact of background
rates of adverse fetal outcomes which apply to all pregnancies.

In inflammatory bowel disease, the effects of active inflammation on the fetus are believed to be
more harmful than those of drug treatment, and therapy is often justified to induce or maintain
remission during pregnancy. The choice of appropriate treatment is determined by the severity of
the disease and the potential for drug toxicity.

No causal relationship has been established between exposure to sulfasalazine or other 5-

aminosalicylic acid drugs and the development of congenital malformations. These drugs may be
used with relative safety during pregnancy and lactation. Considerable experience with
corticosteroids have shown them to pose very small risk to the developing fetus. Current
evidence indicates that maternal use of azathioprine is not associated with an increased risk of
congenital malformations, though impaired fetal immunity, growth retardation or prematurity is
occasionally observed. Preliminary evidence derived from patients with inflammatory bowel
disease show no significant fetal toxicity following first trimester exposure to mercaptopurine,
though its elective use in pregnancy is controversial. Cyclosporin is not teratogenic, but may be
associated with growth retardation and prematurity. Pregnancy should be avoided in women
treated with methotrexate because of its known abortifacient effects and risk of causing typical
malformations. Although treatment with metronidazole or ciprofloxacin for short durations
appear to be devoid of adverse fetal reactions, the effect of prolonged exposure as required in
Crohn's disease remains unknown.
Treatment of Cardiac Arrhythmias During Pregnancy: Safety Considerations

Abstract:

Maternal and fetal arrhythmias occurring during pregnancy may jeopardise the life of the mother
and the fetus. When arrhythmias are well tolerated and patients are minimally symptomatic,
conservative therapy, such as observation and rest or vagal manoeuvres, should be employed.
When arrhythmias cause debilitating symptoms or haemodynamic compromise, antiarrhythmic
drug therapy is indicated. Although no antiarrhythmic drug is completely safe during pregnancy,
most are well tolerated and can be given with relatively low risk.

Physiological changes that occur during pregnancy mandate caution when administering
antiarrhythmic drugs, with close monitoring of serum concentration and patient response. Drug
therapy should be avoided during the first trimester of pregnancy if possible, and drugs with the
longest record of safety should be used as first-line therapy.

Several therapeutic options exist for most arrhythmias in the mother and fetus. Of the class IA
agents, quinidine has the longest record of safety during pregnancy, and is generally well
tolerated. Procainamide is also well tolerated, and should be a first line option for acute treatment
of undiagnosed wide complex tachycardia. All IA agents should be administered in the hospital
under cardiac monitoring due to the potential risk of ventricular arrhythmias (torsade de pointes).

The IB agent, lidocaine (lignocaine), has local anaesthetic role but is also generally well tolerated
as an antiarrhythmic agents. Phenytoin should be avoided due to the high risk of congenital
malformations and limited role as an antiarrhythmic drug. Of the IC agents, flecainide has been
shown to be very effective in treating fetal supraventricular tachycardia complicated by hydrops.
-Blockers are generally well tolerated and can be used with relative safety in pregnancy,
although recent data suggest that they may cause intrauterine growth retardation if they are
administered during the first trimester.

Amiodarone, a class II agents with characteristics of the other antiarrhythmic drug classes, has
been reported to cause congenital abnormalities; it should be avoided during the first trimester
and used only to treat life-threatening arrhythmias that fail to respond to other therapies.
Adenosine is generally safe to use in pregnancy, and is the drug of choice for acute termination
of maternal supraventricular tachycardia. Digoxin has a long track record of treating both
maternal and fetal arrhythmias, and is one of the safest antiarrhythmics to use during pregnancy.

Direct current cardioversion to terminate maternal arrhythmias is well tolerated and effective,
and should not be delayed if indicated. The use of an implantable cardioverter-defibrillator
should be considered for women of childbearing potential with life-threatening ventricular
arrhythmias.
The Safety of Newer Antidepressants in Pregnancy and Breastfeeding

Abstract:

The pregnancy and postpartum periods are considered to be relatively high risk times for
depressive episodes in women, particularly for those with pre-existing psychiatric illnesses.
Therefore, it may be necessary to start or continue the pharmacological treatment of depression
during these two timeframes. Hence, the aim of this review is to examine the effects on the fetus
and infant of exposure, through the placenta and maternal milk, to the following drugs:
fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, mirtazapine,
venlafaxine, reboxetine and bupropion.
The teratogenic risks, perinatal toxicity and effects on the neurobehavioural development of
newborns associated with exposure through the placenta or maternal milk to these medications
need to be carefully assessed before starting psychopharmacological treatment in pregnant or
lactating women. In spite of the limitations of some of the studies reviewed, the older selective
serotonin-reuptake inhibitors (SSRIs) [as we await further data regarding escitalopram] and
venlafaxine seem to be devoid of teratogenic risks. By contrast, the data concerning possible
consequences related to exposure to SSRIs via the placenta and breastmilk on neonatal
adaptation and long-term neurocognitive infant’s development are still controversial.
Nevertheless, a number of reports have shown that an association between placental exposure to
SSRIs and adverse but self-limiting effects on neonatal adaptation may exist. In addition, the
information on both teratogenic and functional teratogenic risks associated with exposure to
bupropion, mirtazapine and reboxetine is incomplete or absent; at present, these compounds
should not be used as first-line agents in the pharmacological treatment of depression in
pregnancy and breastfeeding.
Untreated depression is not without its own risks since mothers affected by depression have a
negative impact on the emotional development of their children and major depression, especially
when complicated by a delusional component, may lead to the mother attempting suicide and
infanticide. Consequently, clinicians need to help mothers weigh the risks of prenatal exposure to
drugs for their babies against the potential risks of untreated depression and abrupt
discontinuation of pharmacological treatment. Given these situations, we suggest that choosing
to administer psychopharmacological treatment in pregnant or breastfeeding women with
depression will result primarily from a careful evaluation of their psychopathological condition;
currently, the degree of severity of maternal disease appears to represent the most relevant
parameter to take this clinical decision.
Treating Allergic Rhinitis in Pregnancy: Safety Considerations

Abstract:

Allergic rhinitis affects approximately one-third of women of childbearing age. As a result,

symptoms ranging from sneezing and itching to severe nasal obstruction may require
pharmacotherapy. However, product labels state that medications for allergic rhinitis should be
avoided during pregnancy due to lack of fetal safety data, even though the majority of the agents
have human data which refute these notions. We present a systematic and critical review of the
medical literature on the use of pharmacotherapy for the management of allergic rhinitis during
pregnancy. Electronic databases and other literature sources were searched to identify
observational controlled studies focusing on the rate of fetal malformations in pregnant women
exposed to agents used to treat allergic rhinitis and related diseases compared with controls.

Immunotherapy and intranasal sodium cromoglycate (cromolyn) and beclomethasone would be

considered as first-line therapy, both because of their lack of association with congenital
abnormalities and their superior efficacy to other agents. First-generation (e.g. chlorpheniramine)
and second-generation (e.g. cetirizine) antihistamines have not been incriminated as human
teratogens. However, first-generation antihistamines are favoured over their second generation
counterparts based on their longevity, leading to more conclusive evidence of safety. There are
no controlled trials with loratadine and fexofenadine in human pregnancy.

Oral, intranasal and ophthalmic decongestants (e.g. pseudoephedrine, phenylephrine and

oxymetazoline, respectively) should be considered as second-line therapy, although further
studies are needed to clarify their fetal safety. No human reproductive studies have been reported
with the ophthalmic antihistamines ketorolac and levocabastine, although preliminary data
reported suggest no association between pheniramine and congenital malformations. There are
no documented epidemiological studies with intranasal corticosteroids (e.g. budesonide,
fluticasone propionate, mometasone) during pregnancy; however, inhaled corticosteroids (e.g.
beclomethasone) have not been incriminated as teratogens and are commonly used by pregnant
women who have asthma.

In summary, women with allergic rhinitis during pregnancy can be treated with a number of
pharmacological agents without concern of untoward effects on their unborn child. Although the
choice of agents in part should be based on evidence of fetal safety, issue of efficacy needs to be
addressed in order to optimally manage this condition.
Safety of azathioprine in pregnancy in inflammatory bowel disease.

Department of Gastroenterology, St. Bartholomew's, Hospital, London, England.

Abstract

Although azathioprine has been reported to be safe during pregnancy in renal transplant
recipients and patients with systemic lupus erythematosus, opinions vary whether it should be
continued in pregnancy in inflammatory bowel disease. A retrospective analysis of the outcome
of 16 pregnancies in 14 women receiving azathioprine for inflammatory bowel disease was
performed. There was one infective complication of pregnancy (hepatitis B virus infection), but
there were no congenital abnormalities or subsequent health problems in the children. This
preliminary study suggests that azathioprine is safe in pregnancy in inflammatory bowel disease
patients and that termination of pregnancy is not mandatory for those who conceive while taking
the drug.
The safety of antimalarial drugs in pregnancy.

Division of Control of Tropical Diseases, World Health Organization, Switzerland.

Abstract

Alternative drugs to chloroquine are required to prevent the deleterious effects of malaria in
pregnancy. Fear of potential toxicity has limited antimalarial drug use in pregnancy. Animal
toxicity studies have documented teratogenicity when antimalarials are administered at high
dosages. Excepting the tetracyclines, there is no evidence to suggest that, at standard dosages,
any of the antimalarial drugs are teratogenic. Primaquine is not recommended because of the
potential risk of haemolytic effects in the fetus. Rates of spontaneous abortion and birth defects
were comparable in pregnant women taking mefloquine, compared with chloroquine-proguanil,
or pyrimethamine-sulfadoxine prophylaxis, in the first trimester of pregnancy. Standard doses of
quinine do not increase the risk of abortion or preterm delivery. Therapeutic mefloquine does not
provoke hypoglycaemia. There is no evidence in the literature to support the hypothetical risk of
kernicterus in the newborn, following exposure to antimalarial drugs containing sulphonamides
or sulphones prior to delivery. Documentation of the safety of doxycycline, halofantrine, and the
artemisinin derivatives in the treatment of malaria in pregnant women is currently limited.
Depression in Pregnancy: Drug Safety and Nursing Management

Abstract

Women who are already predisposed to depression are at increased risks during pregnancy
because of endocrine changes; untreated depression in pregnant women might lead to adverse
effects for both mothers and infants. This article examines outcomes associated with the use of
antidepressants during pregnancy and identifies how nurses can help depressed pregnant women.

It is recommended that pregnant women who have mild depression be treated with
nonpharmacologic therapy, such as counseling, cognitive-behavioral therapy, or interpersonal
psychotherapy. Current appropriate treatment for pregnant women with moderate and severe
depression is antidepressant medication, although there is no consensus on the best
antidepressants for use in pregnancy. Thus, the psychotropic drug must be chosen carefully to
minimize negative effects on infants and mothers, for some studies have demonstrated
deleterious effects on infants.

Nurses in multiple settings who interact with pregnant women should be aware of the necessity
of screening for depression. Nurses in antenatal care settings can refer appropriately screened
women to mental health specialists; psychiatric nurse practitioners can identify suitable
interventions based on potential risks and benefits to maternal and infant health.
Risks and Benefits of Nicotine to Aid Smoking Cessation in Pregnancy

Abstract:

Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related
morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who
wish to quit smoking from doing so. The safety and efficacy of nicotine replacement therapy
(NRT) for smoking cessation during pregnancy have not been well studied.

Nicotine is classified by the US Food and Drug Administration as a Pregnancy Category D drug.
Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine
effects on the brain may be involved in the pathophysiology of sudden infant death syndrome
(SIDS). It has been assumed that the cardiovascular effects of nicotine resulting in reduced blood
flow to the placenta (uteroplacental insufficiency) is the predominant mechanism of the
reproductive toxicity of cigarette smoking during pregnancy. Short term high doses of nicotine in
pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However,
studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal
effects upon the maternal and fetal cardiovascular systems.

Cigarette smoking delivers thousands of chemicals, some of which are well documented
reproductive toxins (e.g. carbon monoxide and lead). A myriad of cellular and molecular
biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant
women who smoke. The cumulative abnormalities produced by the various toxins in cigarette
smoke are probably responsible for the numerous adverse reproductive outcomes associated with
smoking. It is doubtful that the reproductive toxicity of cigarette smoking is primarily related to
nicotine.

We recommend the following. Efficacy trials of NRT as adjunctive therapy for smoking
cessation during pregnancy should be conducted. The initial dose of nicotine in NRT should be
similar to the dose of nicotine that the pregnant woman received from smoking. Intermittent-use
formulations of NRT (gum, spray, inhaler) are preferred because the total dose of nicotine
delivered to the fetus will be less than with continuous-use formulations (transdermal patch). A
national registry for NRT use during pregnancy should be created to prospectively collect
obstetrical outcome data from NRT efficacy trials and from individual use. The goal of this
registry would be to determine the safety of NRT use during pregnancy, especially with respect
to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that
minimal amounts of nicotine are excreted into breast milk and that NRT can be safely used by
breast-feeding mothers.
The role of pharmacoepidemiology in pharmacovigilance: rational drug use in pregnancy

Abstract

The most important objective of the Hungarian Case–Control Surveillance of Congenital

Abnormalities is the postmarketing surveillance of the teratogenic effects of drugs. This dataset
includes 22,865 pregnant women who had offspring with congenital abnormalities and 38,151
pregnant women who had healthy babies between 1980 and 1996. Their case–control analysis is
appropriate to assess the risks and benefits of drug treatments during pregnancy. Of about 4000
drugs used in Hungary, 35 seemed to be human teratogens. Only a small proportion (about 1%)
of congenital abnormalities is traceable to teratogenic drugs in humans. Hungarian studies were
not able to confirm the teratogenicity of tetracyclines (doxycycline) and some other drugs, but
indicated the beneficial effect of clotrimazole in the prevention of undescended testis related to
preterm birth. Periconceptional multivitamin/folic acid supplementation can reduce the first
occurrence of neural-tube defects, oral clefts, cardiovascular malformations, and urinary tract
defects. At present the teratogenicity of drugs is exaggerated and the benefits of drug treatment
during pregnancy are underestimated. This unbalanced risk–benefit assessment initiated
disadvantageous decisions, e.g. planned pregnancies are terminated because of the supposed
false teratogenic risk of drugs; pregnant women with acute or chronic diseases are not treated
adequately and it causes exacerbation of the illness or fetal complications; the necessary drug
treatments are connected with a permanent psychological stress. In conclusion, the anxiety and
fear created by the notion that nearly all drugs cause congenital abnormalities is more harmful
than the effect of proven human teratogenic drugs themselves. Copyright © 1999 John Wiley &
Sons, Ltd.
Antimalarial Drug Toxicity: A Review

Abstract:

Malaria, caused mostly by Plasmodium falciparum and P. vivax, remains one of the most
important infectious diseases in the world. Antimalarial drug toxicity is one side of the risk-
benefit equation and is viewed differently depending upon whether the clinical indication for
drug administration is malaria treatment or prophylaxis. Drug toxicity must be acceptable to
patients and cause less harm than the disease itself. Research that leads to drug registration tends
to omit two important groups who are particularly vulnerable to malaria – very young children
and pregnant women. Prescribing in pregnancy is a particular problem for clinicians because the
risk-benefit ratio is often very unclear.
The number of antimalarial drugs in use is very small. Despite its decreasing efficacy against P.
falciparum, chloroquine continues to be used widely because of its low cost and good
tolerability. It remains the drug of first choice for treating P. vivax malaria. Pruritus is a common
adverse effect in African patients. As prophylaxis, chloroquine is usually combined with
proguanil. This combination has good overall tolerability but mouth ulcers and gastrointestinal
upset are more common than with other prophylactic regimens. Sulfadoxine/pyrimethamine is
well tolerated as treatment and when used as intermittent preventive treatment in pregnant
African women. Sulfadoxine/pyrimethamine is no longer used as prophylaxis because it may
cause toxic epidermal necrolysis and Stevens Johnson syndrome. Mefloquine remains a valuable
drug for prophylaxis and treatment. Tolerability is acceptable to most patients and travellers
despite the impression given by the lay press. Dose-related serious neuropsychiatric toxicity can
occur; mefloquine is contraindicated in individuals with a history of epilepsy or psychiatric
disease. Quinine is the mainstay for treating severe malaria in many countries. Cardiovascular or
CNS toxicity is rare, but hypoglycaemia may be problematic and blood glucose levels should be
monitored. Halofantrine is unsuitable for widespread use because of its potential for
cardiotoxicity.
There is renewed interest in two old drugs, primaquine and amodiaquine. Primaquine is being
developed as prophylaxis, and amodiaquine, which was withdrawn from prophylactic use
because of neutropenia and hepatitis, is a potentially good partner drug for artesunate against
falciparum malaria. Atovaquone/proguanil is a new antimalarial combination with good efficacy
and tolerability as prophylaxis and treatment. The most important class of drugs that could have
a major impact on malaria control is the artemisinin derivatives. They have remarkable efficacy
and an excellent safety record. They have no identifiable dose-related adverse effects in humans
and only very rarely produce allergic reactions. Combining an artemisinin derivative with
another efficacious antimalarial drug is increasingly being viewed as the optimal therapeutic
strategy for malaria.
Treating Gastro-Oesophageal Reflux Disease During Pregnancy and Lactation: What are
the Safest Therapy Options?

Abstract:

Gastro-oesophageal reflux and heartburn are reported by 45 to 85% of women during pregnancy.
Typically, the heartburn of pregnancy is new onset and is precipitated by the hormonal effects of
estrogen and progesterone on lower oesophageal sphincter function. In mild cases, the patient
should be reassured that reflux is commonly encountered during a normal pregnancy: lifestyle
and dietary modifications may be all that are required.

In a pregnant woman with moderate to severe reflux symptoms, the physician must discuss with
the patient the benefits versus the risks of using drug therapy. Medications used for treating
gastro-oesophageal reflux are not routinely or vigorously tested in randomised, controlled trials
in women who are pregnant because of ethical and medico-legal concerns. Safety data are based
on animal studies, human case reports and cohort studies as offered by physicians,
pharmaceutical companies and regulatory authorities.

If drug therapy is required, first-line therapy should consist of nonsystemically absorbed

medications, including antacids or sucralfate, which offer little, if any, risk to the fetus. Systemic
therapy with histamine H receptor antagonists (avoiding nizatidine) or prokinetic drugs
(metoclopramide, cisapride) should be reserved for patients with more severe symptoms. Proton
pump inhibitors are not recommended during pregnancy except for severe intractable cases of
gastro-oesophageal reflux or possibly prior to anaesthesia during labour and delivery. In these
rare situations, animal teratogenicity studies suggests that lansoprazole may be the best choice.
Use of the least possible amount of systemic drug needed to ameliorate the patient's symptoms is
clearly the best for therapy. If reflux symptoms are intractable or atypical, endoscopy can safely
be performed with conscious sedation and careful monitoring the mother and fetus.
Antiretroviral Therapy in Pregnancy: A Focus on Safety

Abstract:

Antiretroviral compounds differ from most other new pharmaceutical agents in that they have
become widely prescribed in pregnancy in the absence of proof of safety. They are prescribed for
the treatment of the mother and to reduce the risk of transmission of HIV to the fetus. In the
animal models tested to date, no increased risk of malformations has been demonstrated for some
compounds whereas others have been associated with malformations or developmental
abnormalities in rats, mice or rabbits and, in the case of efavirenz, monkeys.

Zidovudine monotherapy is still prescribed to reduce the risk of mother-to-child transmission of

HIV. Combinations of 3 or more compounds are recommended when treatment of the mother is
deemed necessary because of advanced HIV infection. Until recently, in vitro toxicity studies
relevant to pregnancy were restricted to single agents; no animal teratogenicity or carcinogenesis
studies of combination therapy have been published.

Despite many thousands of women having taken antiretroviral therapy to reduce the risk of
transmission, documented experience in human pregnancy remains sadly lacking, with the
possible exception of zidovudine which has been prescribed in clinical trials to several hundred
mother-infant pairs. For other compounds and for the numerous permutations of combination
therapy, data are available only from small phase I/II studies, from retrospective investigations
and from the prospective arm of the Antiretroviral Pregnancy Register (i.e. pregnancies in
women taking antiretrovirals who were registered before delivery and then followed up).

Antiretroviral monotherapy and combination therapy is widely prescribed in pregnancy because:

 with appropriate management, which includes antiretroviral therapy, the risk of mother-
to-child transmission can be reduced from 15 to 25% to less than 1%;
 pregnant women with advanced HIV infection require therapy;
 combination therapy with at least 3 compounds significantly reduces morbidity and
mortality compared with dual or monotherapy; and
 the benefits of therapy for both the mother and the infant outweigh the risk.

The choice of antiretroviral therapy in pregnancy may be influenced by the indication

(prevention of transmission or maternal treatment), past antiretroviral therapy exposure/drug
resistance, effects of pregnancy on the pharmacokinetics of the drug and factors influencing
tolerability and adherence. In pregnancy, tolerability may be even more important than usual,
especially if therapy exacerbates common complications of pregnancy, such as vomiting and
glucose intolerance.